RESUMO
INTRODUCTION: The baboon is a well-characterized model of human early stage atherosclerosis. However, histological and morphological changes involved in atherogenesis in baboons are not known. Previously, we challenged baboons with a high-cholesterol, high-fat diet for two years and observed fatty streak and plaque lesions in iliac arteries (RCIA). METHODS: We evaluated histological and morphological changes of baboon arterial lesions and control arteries. In addition, we evaluated the vascular expression of CD68 and SMαA markers with progression of atherosclerosis. RESULTS: We observed changes that correlated with extent of atherosclerosis, including increased maximum intimal thickness. We demonstrated at molecular level the infiltration of smooth muscle cells and macrophages into the intimal layer. Further, we observed histological and morphological discordancy between the affected and adjacent areas of the same RCIA. CONCLUSION: Atherogenesis in baboons is accompanied by histological, morphological, and molecular changes, as in humans, providing insights to evaluate the mechanisms underlying early stage atherosclerosis in target tissues.
Assuntos
Aterosclerose/patologia , Colesterol/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Artéria Ilíaca/patologia , Animais , Aterosclerose/etiologia , Papio hamadryasRESUMO
Cutaneous epitheliotropic lymphoma (CEL) has not been reported in non-human primates. We report the first case of CEL in a 9-year-old baboon. The phenotype of the neoplastic cells in this baboon is similar to CEL in humans (CD3+, CD4+, CD8-) and different from dogs (CD3+, CD4-, CD8+).
Assuntos
Linfoma Cutâneo de Células T/veterinária , Doenças dos Macacos/diagnóstico , Papio , Animais , Animais de Zoológico , Feminino , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/etiologia , Doenças dos Macacos/etiologiaRESUMO
Multiple endocrine neoplasia (MEN) has not been reported in baboons, but this condition is well described in humans. An internal database was searched for all cases of concurrent endocrine hyperplasia and neoplasia in baboons. Twenty-four baboons (Papio spp.) with concurrent endocrine hyperplasia and neoplasia were identified. Twenty-one baboons had lesions in two endocrine organs, two baboons had lesions in three organs, and one baboon had lesions in four organs. Ten baboons aligned with the MEN1 classification; 14 baboons did not match any current human MEN classification. We report 24 cases of MEN-like syndrome in baboons. MEN1-like lesions accounted for nearly half (41%) of the affected animals. Genetic analysis of baboons with MEN-like syndrome could further elucidate the mechanisms of MEN and support the use of baboons as animal models for human MEN.
Assuntos
Doenças dos Macacos/patologia , Neoplasia Endócrina Múltipla/patologia , Papio , Animais , Animais de Laboratório , Feminino , Masculino , Doenças dos Macacos/classificação , Neoplasia Endócrina Múltipla/classificação , Estudos Retrospectivos , Síndrome , TexasRESUMO
BACKGROUND: The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non-human primate model. METHODS: We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy. RESULTS: We observed evidence of atherosclerosis in all but one baboon fed the two-year challenge diet. CVD risk biomarkers, the prevalence, size, and complexity of arterial lesions, plus consequent arterial stiffness, were increased in comparison with dietary control animals. CONCLUSIONS: Feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans.
Assuntos
Aterosclerose/etiologia , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Papio anubis , Papio cynocephalus , Animais , Artérias/fisiologia , Artérias/fisiopatologia , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Feminino , Lipoproteínas/metabolismo , MasculinoRESUMO
Coccidioidomycosis in nonhuman primates has been sporadically reported in the literature. This study describes 22 cases of coccidioidomycosis in nonhuman primates within an endemic region, and 79 cases of coccidioidomycosis from the veterinary literature are also reviewed. The 22 cases included baboons ( n = 10), macaques ( n = 9), and chimpanzees ( n = 3). The majority died or were euthanized following episodes of dyspnea, lethargy, or neurologic and locomotion abnormalities. The lungs were most frequently involved followed by the vertebral column and abdominal organs. Microscopic examination revealed granulomatous inflammation accompanied by fungal spherules variably undergoing endosporulation. Baboons represented a large number of cases presented here and had a unique presentation with lesions in bone or thoracic organs, but none had both intrathoracic and extrathoracic lesions. Although noted in 3 cases in the literature, cutaneous infections were not observed among the 22 contemporaneous cases. Similarly, subclinical infections were only rarely observed (2 cases). This case series and review of the literature illustrates that coccidioidomycosis in nonhuman primates reflects human disease with a varied spectrum of presentations from localized lesions to disseminated disease.
Assuntos
Coccidioidomicose/veterinária , Doenças dos Primatas/patologia , Animais , Coccidioidomicose/microbiologia , Coccidioidomicose/patologia , Feminino , Pulmão/patologia , Macaca/microbiologia , Masculino , Microscopia Eletrônica/veterinária , Pan troglodytes/microbiologia , Papio/microbiologia , Reação em Cadeia da Polimerase/veterinária , Doenças dos Primatas/microbiologiaRESUMO
BACKGROUND: Myeloid sarcoma is a rare manifestation of myeloproliferative disorder defined as an extramedullary mass composed of myeloid precursor cells. A 9-month old, female, common marmoset (Callithrix jacchus) had increased respiratory effort. METHODS: A complete necropsy with histology and immunohistochemistry was performed. RESULTS: The thymus was replaced by a firm, gray-tan mass with a faint green tint, filling over 50% of the thoracic cavity. Sheets of granulocytes, lymphoid cells, nucleated erythrocytes, megakaryocytes, and hematopoietic precursors of indeterminate cell lineage replaced the thymus, perithymic connective tissue, mediastinal adipose tissues, epicardium, and much of the myocardium. The cells demonstrated diffuse strong cytoplasmic immunoreactivity for lysozyme, and strong, multifocal membranous immunoreactivity for CD117. CONCLUSION: We report the first case of a myeloid sarcoma in a common marmoset (C. jacchus), similar to reported human cases of mediastinal myeloid sarcoma, and present a review of myeloproliferative diseases from the veterinary literature.
Assuntos
Callithrix , Neoplasias do Mediastino/veterinária , Doenças dos Macacos/diagnóstico , Doenças dos Macacos/etiologia , Sarcoma Mieloide/veterinária , Animais , Feminino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/etiologia , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/etiologiaRESUMO
Rhesus macaques experimentally infected with Simian Immunodeficiency Virus (SIV) experience immunosuppression and often opportunistic infection. Among the most common opportunistic infections are rhesus cytomegalovirus (RhCMV), a ubiquitous betaherpesvirus that undergoes continuous low-level replication in immunocompetent monkeys. Upon SIV-mediated immunodeficiency, RhCMV reactivates and results in lesions in numerous organ systems including the nervous and reproductive systems. We report the first case of cytomegaloviral hypophysitis in a SIV-immunocompromised rhesus macaque.
Assuntos
Citomegalovirus/isolamento & purificação , Hipofisite/imunologia , Hospedeiro Imunocomprometido , Macaca mulatta , Infecções Oportunistas/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Animais , Feminino , Hipofisite/complicações , Hipofisite/virologia , Infecções Oportunistas/complicações , Infecções Oportunistas/virologia , Vírus da Imunodeficiência Símia/fisiologiaRESUMO
We present the spontaneous causes of mortality for 137 chimpanzees (Pan troglodytes) over a 35-year period. A record review of the pathology database was performed and a primary cause of mortality was determined for each chimpanzee. The most common causes of mortality were as follows: cardiomyopathy (40% of all mortalities), stillbirth/abortion, acute myocardial necrosis, chimpanzee-induced trauma, amyloidosis, and pneumonia. Five morphologic diagnoses accounted for 61% of mortalities: cardiomyopathy, hemorrhage, acute myocardial necrosis, amyloidosis, and pneumonia. The most common etiologies were degenerative, undetermined, bacterial, traumatic, and neoplastic. The cardiovascular system was most frequently involved, followed by the gastrointestinal, respiratory, and multisystemic diseases. Degenerative diseases were the primary etiological cause of mortality of the adult captive chimpanzee population. Chimpanzee-induced trauma was the major etiological cause of mortality among the perinatal and infant population. This information should be a useful resource for veterinarians and researchers working with chimpanzees.
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Doenças dos Símios Antropoides/mortalidade , Causas de Morte , Pan troglodytes , Animais , Animais de Laboratório , Doenças dos Símios Antropoides/etiologia , Masculino , Texas/epidemiologiaRESUMO
We present the spontaneous pathological lesions identified as a result of necropsy or biopsy for 245 chimpanzees (Pan troglodytes) over a 35-year period. A review of the pathology database was performed for all diagnoses on chimpanzees from 1980 to 2014. All morphologic diagnoses, associated system, organ, etiology, and demographic information were reviewed and analyzed. Cardiomyopathy was the most frequent lesion observed followed by hemosiderosis, hyperplasia, nematodiasis, edema, and hemorrhage. The most frequently affected systems were the gastrointestinal, cardiovascular, urogenital, respiratory, and lymphatic/hematopoietic systems. The most common etiology was undetermined, followed by degenerative, physiologic, neoplastic, parasitic, and bacterial. Perinatal and infant animals were mostly affected by physiologic etiologies and chimpanzee-induced trauma. Bacterial and physiologic etiologies were more common in juvenile animals. Degenerative and physiologic (and neoplastic in geriatric animals) etiologies predominated in adult, middle aged, and geriatric chimpanzees.
Assuntos
Doenças dos Símios Antropoides/patologia , Pan troglodytes , Animais , Doenças dos Símios Antropoides/epidemiologia , Doenças dos Símios Antropoides/etiologia , Biópsia/veterinária , IncidênciaRESUMO
UNLABELLED: This study addresses the role of Ebola virus (EBOV) specific infectivity in virulence. Filoviruses are highly lethal, enveloped, single-stranded negative-sense RNA viruses that can cause hemorrhagic fever. No approved vaccines or therapies exist for filovirus infections, and infectious virus must be handled in maximum containment. Efficacy testing of countermeasures, in addition to investigations of pathogenicity and immune response, often requires a well-characterized animal model. For EBOV, an obstacle in performing accurate disease modeling is a poor understanding of what constitutes an infectious dose in animal models. One well-recognized consequence of viral passage in cell culture is a change in specific infectivity, often measured as a particle-to-PFU ratio. Here, we report that serial passages of EBOV in cell culture resulted in a decrease in particle-to-PFU ratio. Notably, this correlated with decreased potency in a lethal cynomolgus macaque (Macaca fascicularis) model of infection; animals were infected with the same viral dose as determined by plaque assay, but animals that received more virus particles exhibited increased disease. This suggests that some particles are unable to form a plaque in a cell culture assay but are able to result in lethal disease in vivo. These results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures. IMPORTANCE: Ebola virus (EBOV) can cause severe hemorrhagic disease with a high case-fatality rate, and there are no approved vaccines or therapies. Specific infectivity can be considered the total number of viral particles per PFU, and its impact on disease is poorly understood. In stocks of most mammalian viruses, there are particles that are unable to complete an infectious cycle or unable to cause cell pathology in cultured cells. We asked if these particles cause disease in nonhuman primates by infecting monkeys with equal infectious doses of genetically identical stocks possessing either high or low specific infectivities. Interestingly, some particles that did not yield plaques in cell culture assays were able to result in lethal disease in vivo. Furthermore, the number of PFU needed to induce lethal disease in animals was very low. Our results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures.
Assuntos
Ebolavirus/fisiologia , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/virologia , Animais , Modelos Animais de Doenças , Ebolavirus/crescimento & desenvolvimento , Ebolavirus/patogenicidade , Haplorrinos , Doença pelo Vírus Ebola/mortalidade , Macaca fascicularis , Inoculações Seriadas , Análise de Sobrevida , Carga Viral , Ensaio de Placa Viral , VirulênciaRESUMO
In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a ß-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.
Assuntos
Hipoglicemiantes/administração & dosagem , Inflamação/patologia , Pâncreas Exócrino/patologia , Ductos Pancreáticos/patologia , Peptídeos/administração & dosagem , Peçonhas/administração & dosagem , Amilases/sangue , Animais , Apoptose , Exenatida , Feminino , Hiperplasia , Hipoglicemiantes/efeitos adversos , Imuno-Histoquímica , Infusões Intravenosas , Resistência à Insulina , Antígeno Ki-67/metabolismo , Masculino , Microscopia de Fluorescência , Pâncreas Exócrino/metabolismo , Ductos Pancreáticos/citologia , Papio , Peptídeos/efeitos adversos , Fenótipo , Peçonhas/efeitos adversosRESUMO
BACKGROUND: Crescentic glomeruli are the hallmark finding in rapidly progressive glomerulonephritis (RPGN) and are characterized by disruption and proliferation of the glomerular capsule and an influx of cells into Bowman's space. Pauci-immune-type RPGN is identified by a lack of immunoglobulins and immune complexes in the glomerular basement membrane. METHODS: Complete necropsy and histology were performed on the affected chimpanzee. Electron microscopy was performed on kidney sections. A search of the literature was performed to identify spontaneous RPGN in animals. RESULTS: We report a case of crescentic glomerulonephritis of the pauci-immune-type in a hepatitis C virus-infected 28-year-old male chimpanzee (Pan troglodytes) who was humanely euthanized for a cardiac-related decline in health. CONCLUSION: To our knowledge, this is the first report describing pauci-immune crescentic glomerulonephritis in a non-human primate.
Assuntos
Doenças dos Símios Antropoides , Glomerulonefrite/veterinária , Pan troglodytes , Animais , Animais Domésticos , Animais de Zoológico , Doenças dos Símios Antropoides/diagnóstico , Doenças dos Símios Antropoides/patologia , Glomerulonefrite/classificação , Glomerulonefrite/diagnóstico , Glomerulonefrite/patologia , MasculinoRESUMO
BACKGROUND: We report the causes of mortality for 4350 captive baboons that died or were euthanized due to natural causes during a 23 year period at the Southwest National Primate Research Center. METHODS: Necropsy records were retrieved and reviewed to determine a primary cause of death or indication for euthanasia. Data was evaluated for morphological diagnosis, organ system, and etiology. RESULTS: The 20 most common morphologic diagnoses accounted for 76% of the cases, including stillborn (10.8%); colitis (8.6%); hemorrhage (8.4%); ulcer (5.2%); seizures (4.7%); pneumonia (4.2%); inanition (4.1%); dermatitis (3.8%); spondylosis (3.3%); and amyloidosis (3.0%). The digestive system was most frequently involved (21.3%), followed by the urogenital (20.3%), cardiovascular (12.2%), and multisystem disease (10.3%). An etiology was not identified in approximately one-third of cases. The most common etiologies were trauma (14.8%), degenerative (9.5%), viral (8.7%), and neoplastic/proliferative (7.0%). CONCLUSION: This information should be useful for individuals working with baboons.
Assuntos
Animais de Laboratório , Doenças dos Macacos/mortalidade , Papio , Animais , Feminino , Masculino , Estações do Ano , Texas/epidemiologiaRESUMO
BACKGROUND: An inverse relationship between serum prostate specific antigen (PSA) levels and body mass index (BMI) has been reported in men but not in any animal model. METHODS: Serum PSA in a colony of cynomolgus monkeys was assayed and correlated to body weight, prostate weight, and age. In addition, 15 animals were selected and fed a high sugar high fat (HSHF) diet for 49 weeks to increase their BMI and correlate it to PSA RESULTS: Serum PSA levels were positively correlated to prostate weight (r = 0.515, P = 0.025) and age (r = 0.548, P = 0.00072) but was not significantly correlated to body weight (r = -0.032, P = 0.419). For the animals on the HSHF diet, body weight, lean mass, fat mass, and BMI were significantly higher at 49 weeks than at baseline (P < 0.01). PSA was not significantly correlated to body weight and insulin at both baseline and 49 weeks. PSA was negatively correlated to BMI and insulin resistance (HOMA-IR) at 49 weeks but not at baseline. In addition, we observed hepatic steatosis and increases in serum liver enzymes. CONCLUSIONS: Increases in BMI in cynomolgus monkeys as a result of consuming a HSHF diet resulted in PSA changes similar to those in humans with increased BMI. Cynomolgus monkeys are a useful model for investigating the relationship between obesity, diabetes, and PSA changes resulting from prostate gland pathology.
Assuntos
Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Macaca fascicularis/metabolismo , Obesidade/sangue , Antígeno Prostático Específico/sangue , Absorciometria de Fóton , Animais , Glicemia/análise , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Insulina/sangue , Resistência à Insulina , Masculino , Obesidade/etiologia , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologiaRESUMO
BACKGROUND: Air sacculitis is an important clinical condition in non-human primates. METHODS: We evaluated 37 baboons and seven chimpanzees with spontaneous air sacculitis submitted to pathology over a 20-year period. RESULTS: Air sacculitis was observed almost exclusively in males. Common reported signs were halitosis, coughing, nasal discharges, depression, anorexia, and weight loss. Gross lesions included thickened air sacs and suppurative exudate lining the walls. Microscopic lesions included marked epithelial hyperplasia or hypertrophy, necrosis, fibrosis, cellular infiltrates, and bacterial colonies. Mixed bacterial infections were more common than infections by single species of bacteria. Streptococcus sp. was the most frequent bacteria isolated in both baboons and chimpanzees. CONCLUSIONS: This is the first report describing the gross and microscopic lesions of air sacculitis in chimpanzees. The preponderance of males suggests a male sex predilection in baboons.
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Sacos Aéreos/patologia , Doenças dos Símios Antropoides/patologia , Doenças dos Macacos/patologia , Infecções Respiratórias/veterinária , Sacos Aéreos/microbiologia , Animais , Doenças dos Símios Antropoides/microbiologia , Feminino , Masculino , Doenças dos Macacos/microbiologia , Pan troglodytes , Papio , Infecções Respiratórias/microbiologia , Infecções Respiratórias/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: A comprehensive survey of the prevalence of congenital anomalies in baboons has not been previously reported. We report the congenital anomalies observed over a 26-year period in a large captive baboon colony. METHODS: A computer search was performed for all baboon congenital anomalies identified at necropsy and recorded on necropsy submissions. RESULTS: We identified 198 congenital anomalies in 166 baboons from 9972 necropsies (1.66% of total necropsies). The nervous, urogenital, musculoskeletal, and cardiovascular systems were most commonly affected. The most common organs affected were the brain, bone, heart, testicle, kidney, penis, aorta, and skeletal muscle. The most frequent congenital anomalies were blindness, seizures, and hydrocephalus. CONCLUSIONS: The baboon has an overall frequency of congenital anomalies similar to humans and other non-human primates. Although the most frequently affected systems are similar, congenital anomalies involving the digestive system appear to be less common in the baboon.
Assuntos
Anormalidades Congênitas/veterinária , Papio/anormalidades , Animais , Anormalidades Congênitas/epidemiologia , Feminino , Incidência , Masculino , Prevalência , Texas/epidemiologiaRESUMO
BACKGROUND: Baboons are useful animal models for biomedical research, but the natural pathology of the baboon is not as well defined as other non-human primates. METHODS: A computer search for all morphologic diagnoses from baboon necropsies at the Southwest National Primate Research Center was performed and included all the natural deaths and animals euthanized for natural causes. RESULTS: A total of 10,883 macroscopic or microscopic morphologic diagnoses in 4297 baboons were documented and are presented by total incidence, relative incidence by sex and age-group, and mean age of occurrence. The most common diagnoses in descending order of occurrence were hemorrhage, stillborn, amyloidosis, colitis, spondylosis, and pneumonia. The systems with the most diagnoses were the digestive, urogenital, musculoskeletal, and respiratory. CONCLUSION: This extensive evaluation of the natural pathology of the baboon should be an invaluable biomedical research resource.
Assuntos
Doenças dos Macacos/patologia , Papio , Fatores Etários , Animais , Feminino , Masculino , Fatores SexuaisRESUMO
BACKGROUND: The metabolic syndrome is common in populations exposed to a typical Western diet. There is a lack of an animal model that mimics this condition. METHODS: We fed 15 cynomolgus monkeys ad libitum a high-sugar high-fat (HSHF) diet for 33 weeks. Body weight, body composition, serum lipids, and insulin were measured at baseline and at 33 weeks. RESULTS: The animals tolerated the HSHF diet very well. In the intervention group, total serum cholesterol and low-density lipoprotein cholesterol were 3- and 5-fold higher, respectively, at 33 weeks as compared with their baseline levels. Serum high-density lipoprotein cholesterol and triglycerides were not significantly affected. Dual-energy X-ray absorptiometry (DXA) analysis of the intervention group indicated that the trunk fat mass increased by 187% during this period. CONCLUSIONS: Cynomolgus monkeys should be a useful model for investigating the interactions of diet and other factors such as genetics in the development of the metabolic syndrome.
Assuntos
Biomarcadores/sangue , Composição Corporal , Peso Corporal , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Macaca fascicularis/metabolismo , Síndrome Metabólica/veterinária , Absorciometria de Fóton/veterinária , Animais , Glicemia/análise , Colesterol/sangue , Colesterol/química , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Metabolismo Energético , Insulina/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Modelos Animais , Triglicerídeos/sangueRESUMO
Flaviviruses cause severe disease in humans and are a public health priority worldwide. However, no effective therapies or drugs are commercially available yet. Several flavivirus replicon-based assays amenable to high-throughput screening of inhibitors have been reported recently. We developed and performed a replicon-based high-throughput assay for screening small-molecule inhibitors of yellow fever virus (YFV) replication. This assay utilized packaged pseudoinfectious particles containing a YFV replicon that expresses Renilla luciferase in a replication-dependent manner. Several small-molecule compounds with inhibitory activity at micromolar concentrations were identified in the high-throughput screen. These compounds were subsequently tested for their inhibitory activities against YFV replication and propagation in low-throughput assays. Furthermore, YFV mutants that escaped inhibition by two of the compounds were isolated, and in both cases, the mutations were mapped to the NS4B coding region, suggesting a novel inhibitory target for these compounds. This study opens up new avenues for pursuing the nonenzymatic nonstructural proteins as targets for antivirals against YFV and other flaviviruses.
Assuntos
Antivirais/farmacologia , Genoma Viral/genética , Replicon/genética , Replicação Viral/efeitos dos fármacos , Vírus da Febre Amarela/efeitos dos fármacos , Animais , Linhagem Celular , Cricetinae , Imunofluorescência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vírus da Febre Amarela/genéticaRESUMO
AIMS: Ectopic fat is a recognized contributor to insulin resistance and metabolic dysfunction, while the role of fat deposition inside intestinal wall tissue remains understudied. We undertook this study to directly quantify and localize intramural fat deposition in duodenal tissue and determine its association with adiposity. METHODS: Duodenal tissues were collected from aged (21.2 ± 1.3 years, 19.5 ± 3.1 kg, n = 39) female baboons (Papio sp.). Fasted blood was collected for metabolic profiling and abdominal circumference (AC) measurements were taken. Primary tissue samples were collected at the major duodenal papilla at necropsy: one full cross section was processed for hematoxylin and eosin staining and evaluated; a second full cross section was processed for direct chemical lipid analysis on which percentage duodenal fat content was calculated. RESULTS: Duodenal fat content obtained by direct tissue quantification showed considerable variability (11.95 ± 6.93%) and was correlated with AC (r = 0.60, p < 0.001), weight (r = 0.38, p = 0.02), leptin (r = 0.63, p < 0.001), adiponectin (r = - 0.32, p < 0.05), and triglyceride (r = 0.41, p = 0.01). The relationship between duodenal fat content and leptin remained after adjusting for body weight and abdominal circumference. Intramural adipocytes were found in duodenal sections from all animals and were localized to the submucosa. Consistent with the variation in tissue fat content, the submucosal adipocytes were non-uniformly distributed in clusters of varying size. Duodenal adipocytes were larger in obese vs. lean animals (106.9 vs. 66.7 µm2, p = 0.02). CONCLUSIONS: Fat accumulation inside the duodenal wall is strongly associated with adiposity and adiposity related circulating biomarkers in baboons. Duodenal tissue fat represents a novel and potentially metabolically active site of ectopic fat deposition.